Conformation-Family Monte Carlo (CFMC): An efficient computational method for identifying the low-energy states of a macromolecule

A highly efficient method, Conformation-Family Monte Carlo (CFMC), has been developed for searching the conformational space of a macromolecule and id entifying its low-energy conformations. This method maintains a database of low-energy conformations that are clustered into families. The conformatio ns in this database are improved iteratively by a Metropolis-type Monte Car lo procedure, together with energy minimization, in which the search is bia sed towards investigating the regions of the lowest-energy families. The CF MC method has the advantages of our earlier potential-smoothing methods tin that it 'coarse-grains' the conformational space and exploits information about nearby low-energy states), but avoids their disadvantages (such as th e displacement of the global minimum at large smoothings). The CFMC method is applied to a test protein, domain B of Staphylococcal protein A. Indepen dent CFMC runs yielded the same low-energy families of conformations from r andom starts indicating that the thermodynamically relevant conformational space of this protein has been explored thoroughly. The CFMC method is high ly efficient, performing as well as or better than competing methods, such as Monte Carlo with minimization, conformational-space annealing, and the s elf-consistent basin-to-deformed-basin method.